Chemoproteomic Profiling of Gut Microbiota-Associated Bile Salt Hydrolase Activity
Chemoproteomic Profiling of Gut Microbiota-Associated Bile Salt Hydrolase Activity
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DOI：
10.1021/acscentsci.9b00147
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发表时间：
2019-05-22
影响因子：
18.2
通讯作者：
Chang, Pamela, V
中科院分区：
文献类型：
--
作者：
Parasar, Bibudlia;Zhou, Hao;Chang, Pamela, V
肠道微生物组的宏基因组通过肠道细菌表达的酶的活性编码生物合成和转化小分子代谢物的巨大潜力。因此，阐明这种代谢网络对于理解肠道微生物群如何促进健康和疾病至关重要。首先在肝脏中生物合成的胆汁酸在肠道中被肠道细菌表达的酶修饰成二级胆汁酸，二级胆汁酸调节无数宿主过程，包括脂质代谢、葡萄糖代谢和免疫稳态。次级胆汁酸生物合成的网关反应由胆汁盐水解酶（BSH）介导，BSH是细菌半胱氨酸水解酶，其作用先于肠道内的其他胆汁酸修饰。为了评估由某些肠道微生物群介导的胆汁酸代谢的变化如何影响肠道生理学和病理学，需要直接检查BSH活性的方法，因为它们是肠道胆汁酸代谢的主要调节剂。我们开发了化学蛋白质组学工具来描述肠道微生物组相关BSH活性的变化。我们发现，这些探针可以标记模型微生物中的活性BSH，包括相关的肠道厌氧菌和小鼠肠道微生物组。使用这些工具，我们在炎症性肠病的小鼠模型中确定了BSH活性的改变，在这种情况下，葡聚糖硫酸钠诱导的结肠炎，导致胆汁酸代谢的变化，可能影响宿主的代谢和免疫力。重要的是，我们的研究结果表明，肠道微生物组内BSH酶活性的改变与宏基因组测序确定的基因丰度变化无关，这突出了化学蛋白质组学方法用于询问肠道微生物群代谢活动的实用性。
The metagenome of the gut microbiome encodes tremendous potential for biosynthesizing and transforming small-molecule metabolites through the activities of enzymes expressed by intestinal bacteria. Accordingly, elucidating this metabolic network is critical for understanding how the gut microbiota contributes to health and disease. Bile acids, which are first biosynthesized in the liver, are modified in the gut by enzymes expressed by commensal bacteria into secondary bile acids, which regulate myriad host processes, including lipid metabolism, glucose metabolism, and immune homeostasis. The gateway reaction of secondary bile acid biosynthesis is mediated by bile salt hydrolases (BSHs), bacterial cysteine hydrolases whose action precedes other bile acid modifications within the gut. To assess how changes in bile acid metabolism mediated by certain intestinal microbiota impact gut physiology and pathobiology, methods are needed to directly examine the activities of BSHs because they are master regulators of intestinal bile acid metabolism. Her; we developed chemoproteomic tools to profile changes in gut microbiome-associated BSH activity. We showed that these probes can label active BSHs in model microorganisms, including relevant gut anaerobes, and in mouse gut microbiomes. Using these tools, we identified altered BSH activities in a murine model of inflammatory bowel disease, in this case, colitis induced by dextran sodium sulfate, leading to changes in bile acid metabolism that could impact host metabolism and immunity. Importantly, our findings reveal that alterations in BSH enzymatic activities within the gut microbiome do not correlate with changes in gene abundance as determined by metagenomic sequencing, highlighting the utility of chemoproteomic approaches for interrogating the metabolic activities of the gut microbiota.